Cephalexin is the generic term used to identify the chemical compound 7-(D-.alpha.-aminophenylacetamido)-3-methyl-3-cephem-4-carboxylic acid. The compound is described in U.S. Pat. No. 3,507,861. While cephalexin is a potent antibacterial agent, it does not lend itself to convenient formulation for human therapy because of its physical characteristics. U.S. Pat. No. 3,655,656 describes a process for prreparing a unique form of cephalexin, namely a monohydrate, which is a highly crystalline dense form of cephalexin ideally suited to formulation into capsules and tablets for human therapy.
While cephalexin monohydrate has enjoyed widespread commercial success as a two to four times-a-day treatment for diseases of bacterial origin, it heretofore has not been possible to formulate it into a slow-release rate controlled drug form. It is now recognized that controlling the blood concentrations of a therapeutic agent such as cephalexin over a prolonged period of time is a method of improving the selectivity of the agents' beneficial actions. Moreover, a once or twice-a-day administration of a slow-release dosage form is much more convenient and preferred over the requirement of multiple dosings per day.
A technology involving concepts of an elementary osmotic pump recently has been developed and has proven to be effective in permitting control of drug content and rate of drug delivery in vivo; see Theeuwes, F., "Elementary Osmotic Pump," J. Pharm. Sci., Vol. 64, 1975, pp 1987-1991. In order to function in such a delivery system, a pharmaceutical agent must be sufficiently soluble in water and body fluids to permit development of sufficient differential osmotic pressure to effect release of the active agent into the biological system being treated. The agent must also be of sufficient stability such that it retains its pharmacological potency throughout the entire release period, which may extend from about three to about twelve hours duration.
While cephalexin monohydrate is ideally suited to formulation into conventional dosage forms such as capsules and tablets, it does not lend itself to formulation as a controlled release dosage form employing the osmotic pump technology, primarily because of its relatively low water solubility and the consequent low osmotic pressure of its solutions. Moreover, the low solubility of cephalexin monohydrate delays its absorption so that high blood levels are not immediately realized following administration of conventional formulations.
An object of this invention is to provide a new chemical compound that is a crystalline form of the hydrochloride salt of cephalexin. The new compound has excellent solubility and osmotic pressure characteristics and is ideally suited to formulation as a controlled release dosage form employing the osmotic pump technology. The improved solubility of the compound of this invention permits immediate and improved blood levels following administration of conventional formulations thereof. Another object of the invention is to provide an intermediate that is important in the synthesis of the new compound. A further object of the invention is to provide a process for preparing the new composition of matter and a method for its use.